Method for producing disintegrating particulate composition comprising acid-type carboxymethylcellulose, disintegrating particulate composition comprising acid-type carboxymethylcellulose, and orally disintegrating tablet including disintegrating particulate composition comprising acid-type carboxymethylcellulose

ABSTRACT

An object of the present application is to provide an orally-disintegrating tablet having excellent tablet hardness and disintegrability and a disintegrative particulate composition by which the orally-disintegrating tablet can be obtained with a relatively low tablet compression force and which can provide excellent moldability, as well as a method of producing the same, etc. The present application relates to a method of producing a disintegrative particulate composition including three components consisting of a first disintegrator component of an acid-type carboxymethylcellulose, a second disintegrator component and an excipient, the method including a first wet granulation step using any two of the three components, and a second wet granulation step using granules obtained in the first wet granulation step and the remaining one component of the three components not used in the first wet granulation step; a production method further including a crystalline cellulose as a fourth component; a production method including a third step of mixing a crystalline cellulose into granules obtained in the second wet granulation step; disintegrative particulate compositions obtained by these methods, etc.

This application is a national stage application of International PatentApplication No PCT/JP2013/059083, filed Mar. 27, 2013, which claimspriority to Japanese Patent Application No. 2012-075832, filed Mar. 29,2012; Japanese Patent Application No. 2012-206895, filed Sep. 30, 2012;Japanese Patent Application No. 2012-206896, filed Sep. 30, 2012 andJapanese Patent Application No. 2012-275942, filed Dec. 18, 2012. Theentirety of the aforementioned applications is incorporated herein byreference.

FIELD

The present invention relates to a disintegrative particulatecomposition which includes an acid-type carboxymethylcellulose and whichcan be produced by a multi-stage granulation process, and a method ofproducing the same, as well as an orally-disintegrating tablet includingthe composition.

BACKGROUND

In the past, orally-disintegrating tablets have been developed as highlyconvenient forms which can safely be taken by patients who havedifficulty in swallowing drugs, elderly people, children, etc. and whichcan easily be taken without water. It is important thatorally-disintegrating tablets have sufficient breaking strength (tablethardness) such that any cracks, powdering, etc. are not caused in thetablets during production or transportation of the tablets or duringbreaking the seals in the same manner as general tablets, and also, itis important that orally-disintegrating tablets have excellentdisintegrability (disintegration time) such that the tablets immediatelydisintegrate in the oral cavity.

Moreover, superior moldability has been sought in production of tablets.The term “moldability” here refers to a relation between the tabletcompression force and the tablet hardness resulting therefrom. Inproduction methods which require high tablet compression forces, theremay be problems such as limitations in performance of tablet machines, adecrease in the productivity, and deterioration in functions of coatingfine particles included in tablets. Therefore, it is also important thatparticles or particulate compositions constituting tablets have superiormoldability, i.e. properties that can provide a higher tablet hardnessby using the same tablet compression force or that can achieve the sametablet hardness by a lower tablet compression force.

Tablet hardness and disintegrability are mutually opposing properties.In general, when the molding pressure is increased to increase thehardness, the disintegration time tends to be prolonged, and, when themolding pressure is reduced to shorten the disintegration time, thehardness tends to be smaller. Therefore, various technologies have beendeveloped in order to combine the two properties or to achieve anoptimal balance between the two properties.

Furthermore, components of the particles, granulation methods, etc. havebeen studied in order to impart superior moldability to particles orparticulate compositions constituting tablets.

Additionally, an acid-type carboxymethylcellulose is a cellulosederivative otherwise called “carmellose”, and this substance hasproperties that, when water is added to the substance, the substanceswells but converts into a suspension having almost no viscosity.Therefore, an acid-type carboxymethylcellulose has been used as aningredient for orally-disintegrating tablets, namely as a base, binder,excipient or disintegrator therefor.

Also, a crystalline cellulose is a white water-insoluble powderysubstance obtained by partially depolymerizing α-cellulose, which isobtained from fibrous plants, with acids, followed by purification. Acrystalline cellulose has no taste, and, since the substance ischemically inactive, it does not change even when being mixed withmedicaments. Therefore, a crystalline cellulose has been used forpurposes of a pharmaceutical additive, in particular, an excipient,binder, disintegrator or the like for preparing tablets. In addition, acrystalline cellulose has been used as an emulsification stabilizer orthe like for cosmetics, dairy products, etc. besides an additive forpharmaceuticals.

For example, PTL 1 describes a disintegrative particulate compositionwhich is produced through homogeneous dispersion of mannitol, xylitol,an inorganic excipient, a disintegrator and carmellose in the presenceof water, followed by drying the dispersion. The composition ischaracterized in that composite particles including xylitol dispersed inmannitol particles in the solid state are formed, and that the inorganicexcipient, the disintegrator and carmellose are dispersed in thecomposite particles. The disintegrative particulate composition isproduced through spray granulation of a dispersion obtained bydispersing these components in an aqueous medium, or is produced byspraying the dispersion to carriers such as of mannitol.

Also, PTL 2 describes an orally-disintegrating tablet which contains anactive ingredient and 10% (w/w) or more of carboxymethylcelluloserelative to the total amount. The components are mixed, and then, theorally-disintegrating tablet is prepared with a tablet machine.

Moreover, PTL 3 describes a method of producing an orally-disintegratingtablet which contains loratadine as a medicinal ingredient. Thisproduction method is characterized in that two-stage granulation stepsare carried out therein, i.e. loratadine and at least one type of anadditive such as a binder, excipient, or disintegrator are granulated inthe first granulation step, and, in the second granulation step,granules obtained in the first granulation step are further granulatedtogether with at least one type of the same additive such as a binder,excipient, or disintegrator as that used in the first granulation step.As one example of the disintegrator, carmellose is mentioned therein.

Furthermore, PTL 4 describes a method of producing anorally-disintegrating tablet. The production method includes a step ofspraying a water suspension of a water-soluble but hydrophilicdisintegrating component onto a mixture of an excipient and a medicamentto obtain granules A including the medicament; a step of spraying thesame water suspension of the disintegrating component onto the excipientto obtain granules B not including the medicament; and a step ofsubjecting the resulting granules A and B to compression molding.

CITATION LIST Patent Literature

PTL 1: International Publication Pamphlet No. WO 2011/019045

PTL 2: JP-A-2008-285434

PTL 3: JP-A-2012-31138

PTL 4: Specification of Japanese Patent No. 4551627

DETAILED DESCRIPTION Technical Problem

The problem to be solved by the present invention is to provide adisintegrative particulate composition, including an acid-typecarboxymethylcellulose as a disintegrator component, which can impartexcellent tablet hardness and disintegrability to anorally-disintegrating tablet to which the composition is added, andwhich further imparts, to the orally-disintegrating tablet, excellentmoldability where sufficient tablet hardness can be obtained through themoldability even by a practical and comparatively-low tablet compressionforce in production of the tablet, and to further provide a method ofproducing the same, etc.

In addition, a problem was observed in conventional technologies, inwhich, when producing a disintegrative particulate composition and anorally-disintegrating tablet including the composition, addition of acrystalline cellulose as an excipient increased the tablet hardness butreduced the disintegrability (prolonged the disintegration time).

Accordingly, another object of the present invention is to solve such aproblem, and thus, is to provide a method of producing a disintegrativeparticulate composition which can enhance the tablet hardness whilemaintaining sufficient disintegrability (maintaining the shortdisintegration time) even upon addition of a crystalline cellulose, andto provide a disintegrative particulate composition obtained by theproduction method, as well as an orally-disintegrating tablet includingthe composition, etc.

Solution to Problem

The present inventors carried out intensive studies in order to solvethe above-described problems. Consequently, the present inventors foundthat, in producing a disintegrative particulate composition includingthree components which are a first disintegrator component of anacid-type carboxymethylcellulose, a second disintegrator component otherthan the acid-type carboxymethylcellulose and an excipient, adisintegrative particulate composition providing superior tablethardness and disintegrability, or higher tablet hardness withoutsubstantially prolonging the disintegration time could be produced by amethod mentioned below, as compared with a method in which the threecomponents were used and granulated together in one step, although boththe disintegrative particulate compositions included the samecomponents. That is, said method includes a first wet granulation stepusing any two components of the three components, and a second wetgranulation step using at least granules obtained in the first wetgranulation step and the remaining one component not used in the firstwet granulation step. And also, the present inventors found that thecomposition exhibited higher moldability in production of tablets.

Furthermore, the present inventors found that a disintegrativeparticulate composition having higher tablet hardness while maintainingsufficient disintegrability could be produced by adding a crystallinecellulose as a forth component to the disintegrative particulatecomposition produced in the above-mentioned way, and found thatexcellent tablet hardness and disintegrability were imparted to anorally-disintegrating tablet which was produced by mixing saiddisintegrative particulate composition with a drug. The presentinvention was completed based on these findings.

More specifically, the present invention is to provide the followingembodiments.

Embodiment 1

An method of producing a disintegrative particulate compositionincluding three components consisting of a first disintegrator componentof an acid-type carboxymethylcellulose, a second disintegrator componentother than the acid-type carboxymethylcellulose and an excipient,wherein the method includes a first wet granulation step using any twoof the three components; and a second wet granulation step using atleast granules obtained in the first wet granulation step and theremaining one component not used in the first wet granulation step.

Embodiment 2

The method of producing a disintegrative particulate compositionaccording to Embodiment 1, wherein the disintegrative particulatecomposition further includes a crystalline cellulose as a forthcomponent, and the method includes a first wet granulation step usingany two or three of the four components and a second wet granulationstep using at least the granules obtained in the first wet granulationstep and the remaining one or two of the four components not used in thefirst wet granulation step.

Embodiment 3

The method of producing a disintegrative particulate compositionaccording to Embodiment 1, wherein the disintegrative particulatecomposition further includes a crystalline cellulose as a forthcomponent, and the method includes a first wet granulation step usingany two of the three components other than the crystalline cellulose, asecond wet granulation step using at least the granules obtained in thefirst wet granulation step and the remaining one component not used inthe first wet granulation step, and a third step of mixing thecrystalline cellulose into granules obtained in the second wetgranulation step.

Embodiment 4

The method of producing a disintegrative particulate compositionaccording to any one of Embodiments 1 to 3, wherein any of the fourcomponents is used only in one granulation step.

Embodiment 5

The method of producing a disintegrative particulate compositionaccording to Embodiment 4, wherein the method includes the first wetgranulation step using any two of the three components and the secondwet granulation step using only the granules obtained in the first wetgranulation step and the remaining one component not used in the firstwet granulation step.

Embodiment 6

The method of producing a disintegrative particulate compositionaccording to any one of Embodiments 1 to 5, wherein the seconddisintegrator component is one or more selected from crospovidone,croscarmellose sodium, carboxymethyl starch sodium, low substitutedhydroxypropylcellulose, and carboxymethylcellulose calcium.

Embodiment 7

The method of producing a disintegrative particulate compositionaccording to any one of Embodiments 1 to 6, wherein the excipient is asugar or sugar alcohol.

Embodiment 8

The method of producing a disintegrative particulate compositionaccording to any one of Embodiments 1 to 7, wherein the first and secondwet granulation steps are carried out by a fluidized-bed granulationprocess.

Embodiment 9

The method of producing a disintegrative particulate compositionaccording to any one of Embodiments 1 to 8, wherein the first wetgranulation step is carried out using the first or second disintegratorcomponent and the excipient.

Embodiment 10

The method of producing a disintegrative particulate compositionaccording to any one of Embodiments 1 to 9, wherein a spray liquid iswater or an aqueous solution in which less than 10% of components forthe disintegrative particulate composition are dissolved.

Embodiment 11

A disintegrative particulate composition which is obtained by the methodfor producing a disintegrative particulate composition according to anyone of Embodiments 1 to 10.

Embodiment 12

An orally-disintegrating tablet, including the disintegrativeparticulate composition according to Embodiment 11 and a medicinalingredient.

Embodiment 13

The orally-disintegrating tablet according to Embodiment 12, having ahardness of 45 to 100 N and a disintegration time in water of 10 to 30seconds.

Embodiment 14

The orally-disintegrating tablet according to Embodiment 13, having ahardness of 50 to 100 N, a disintegration time in water of 10 to 30seconds and a disintegration time in the oral cavity of 10 to 30seconds.

Advantageous Effects of Invention

By blending in an orally-disintegrating tablet, the disintegrativeparticulate composition of the present invention, including an acid-typecarboxymethylcellulose as a disintegrator component, excellent tablethardness and disintegrability desired for the orally-disintegratingtablet can be imparted to it, and excellent moldability can be providedin production of said tablet.

Furthermore, by blending a crystalline cellulose in the disintegrativeparticulate composition, more excellent tablet hardness anddisintegrability desired for an orally-disintegrating tablet can beimparted to it, and more excellent moldability can be provided inproduction of said tablet. Such effects are remarkable effects thatcannot be predicted from conventional technologies.

DESCRIPTION OF EMBODIMENTS

The present invention relates to (1) a method of producing adisintegrative particulate composition including three componentsconsisting of a first disintegrator component of an acid-typecarboxymethylcellulose, a second disintegrator component other than theacid-type carboxymethylcellulose and an excipient, characterized byincluding: a first wet granulation step using any two of the threecomponents; and a second wet granulation step using at least granulesobtained in the first wet granulation step and the remaining onecomponent not used in the first wet granulation step (the first methodaccording to the present invention).

The present invention further relates to a method of producing adisintegrative particulate composition including a crystalline celluloseas a forth component besides the above-described three components. Themethod can take the following two embodiments:

(2) a method of producing a disintegrative particulate composition,characterized by including a first wet granulation step using any two orthree of the four components, and a second wet granulation step using atleast granules obtained in the first wet granulation step and theremaining one or two of the four components not used in the first wetgranulation step (the second method of the present invention); and

(3) a method of producing a disintegrative particulate composition,characterized by including a first wet granulation step using any two ofthe three components other than the crystalline cellulose, a second wetgranulation step using at least granules obtained in the first wetgranulation step and the remaining one component not used in the firstwet granulation step, and a third step of mixing the crystallinecellulose into granules obtained in the second wet granulation step (thethird method of the present invention).

Additionally, each of the above-described four components may be usedonly in one granulation step. For example, only granules obtained in thefirst wet granulation step and the remaining component(s) not used inthe first wet granulation step can be used in the second wet granulationstep. Alternatively, one component can be used in a plurality ofgranulation steps. For example, each of components such as crystallinecellulose can be used in both the first and second wet granulationsteps.

Four mechanisms of “wicking”, “swelling”, “deformation” and “repulsion”have been proposed as mechanisms of disintegration of tablets or thelike. Among them, “wicking” is a disintegration mechanism which proceedsupon weakened binding force between particles included in the tablet asa result of water permeation through components such as disintegratorsincluded in the tablet. As a typical example of a disintegrator having ahigher effect to promote such “wicking”, an acid-typecarboxymethylcellulose has been known. Also, “swelling” is adisintegration mechanism which proceeds upon swelling of disintegratorsthemselves as a result of water permeation through the disintegrators.

The acid-type carboxymethylcellulose, which is the first disintegratorcomponent included in the disintegrative particulate composition of thepresent invention, is a substance called carmellose, and has been usedas a pharmaceutical additive. In the same manner as the acid-typecarboxymethylcellulose, for example, both a calcium salt ofcarboxymethylcellulose and a cross-linked product ofcarboxymethylcellulose sodium are water-insoluble, and have been used asdisintegrator for tablets, etc. On the other hand, a sodium salt ofcarboxymethylcellulose is water-soluble, and has been used for purposesof a binder, etc. In addition, in some cases, a salt ofcarboxymethylcellulose may be referred to as carmellose.

For the second disintegrator component of the disintegrative particulatecomposition of the present invention, any disintegrators other than theacid-type carboxymethylcellulose which have been known to a personskilled in the art can be used. However, in order to obtain combinedeffects of the different disintegration mechanisms as shown above, it ispreferable that a disintegrator having a superior effect to promote amechanism other than “wicking” (e.g. “swelling”) be used as the seconddisintegrator component. Suitable examples of such a disintegratorinclude crospovidone, croscarmellose sodium, carboxymethyl starchsodium, low substituted hydroxypropylcellulose, carboxymethylcellulosecalcium, hydroxypropyl starch, and starch. Additionally, crospovidone isa common name for a cross-linked polymer of 1-vinyl-2-pyrrolidone, andcroscarmellose sodium is a common name for a cross-linked product ofcarboxymethylcellulose sodium.

Among them, one, or any combination of two or more selected fromcrospovidone, croscarmellose sodium, carboxymethyl starch sodium, lowsubstituted hydroxypropylcellulose and carboxymethylcellulose calcium ispreferable.

Any compound which has been known to a person skilled in the art as anexcipient is included as the third component in the disintegrativeparticulate composition of the present invention. Typical examples ofsuch a compound include sugars or sugar alcohols such as mannitol,erythritol, sorbitol, D-glucitol (maltitol), xylitol, trehalose, lactoseand maltose. Moreover, as preferable examples thereof, mannitol,erythritol, trehalose, sorbitol and D-glucitol (maltitol) can bementioned. As the excipient, two or more types of compounds properlyselected from these compounds can also be used. Furthermore, whenexcipients are used in each of the first wet granulation step and thesecond wet granulation step, the excipients may be of the same type (thesame combination), or may be of different types (differentcombinations).

The disintegrative particulate composition produced by the method of thepresent invention can include a crystalline cellulose known to a personskilled in the art, as the fourth component. As typical examples of sucha crystalline cellulose, commercially-available products such as“Avicel” (FMC Corporation), “CEOLUS” (Asahi Kasei Chemicals Corp.), and“VIVAPUR” (RETTENMAIER) can be mentioned.

Furthermore, various types of optional components known to a personskilled in the art may properly be added and mixed into thedisintegrative particulate composition of the present invention, for thepurpose of adjusting various characteristics such as the disintegratingforce, binding force and ease in taking the tablet, without impairingthe effects of the present invention according to the above-describedthree or four components. As examples of such components, fluidizingagents, inorganic excipients, sweetening agents, flavoring agents andcoloring agents can be mentioned.

The amount of each component blended in the disintegrative particulatecomposition of the present invention can properly be determined by aperson skilled in the art, depending on, for example, the type of thecomponent, the type and purpose of the medicinal ingredient, which is atarget to be used in the disintegrative particulate composition, or thepurpose of the final product, i.e. the orally-disintegrating tablet. Ingeneral, relative to the total weight of the disintegrative particulatecomposition, the amount of the first disintegrator component is within arange of 10% to 50% by weight, the amount of the second disintegratorcomponent is within a range of 1% to 20% by weight, the amount of thecrystalline cellulose, which is the fourth ingredient, is within a rangeof 1% to 40% by weight, and the amount of the excipient is within arange of 30% to 89% by weight.

It is preferable that the disintegrative particulate composition of thepresent invention have the following physical properties:

(1) an average particle size of 50 to 200 microns, e.g. 50 to 150microns; and

(2) a water content of 0.5% to 6% by weight, e.g. 0.5% to 3% by weight.

In addition, these physical properties are measured by using thefollowing methods and conditions.

The average particle size: 2 g of the disintegrative particulatecomposition is subjected to a measurement with a φ75 mm automaticshaking sieve device (Type “M-2”, Tsutsui Scientific Instruments Co.,Ltd.). In addition, “R” in the present specification means a curvatureradius.

The water content: 5 g of the disintegrative particulate composition issubjected to a measurement using a halogen water content measuringdevice (Type “HB43”, METTLER TOLEDO K.K.).

In each method of the present invention, the first and secondgranulation steps are carried out by a method in which each component isdispersed in the presence of water, and the dispersion is dried to formcomplexes, i.e. by a wet granulation process. As specific examples of awet granulation process, spray methods such as spray drying, tumblinggranulation, agitation granulation and fluidized-bed granulation, thefreeze-drying method, kneading granulation, and the like can bementioned, and the composition can be produced by any of these methodsknown to a person skilled in the art.

Since disintegrators such as an acid-type carboxymethylcellulose arehydrophilic, by carrying out a manipulation of applying a physical forcesuch as by agitation or the like in the presence of water according towet granulation, the aggregated state in the dry powder converts into astate in which particles are more dispersed. Dispersion can most easilybe carried out by the fluidized-bed granulation process in whichdispersion by water spraying and drying are carried out, spray drying,tumbling granulation, agitation granulation, etc., and also, dryingspeeds in these methods are high. Therefore, these methods arepreferable.

Among them, the fluidized-bed granulation process is a granulationmethod in which water, an aqueous solution including a binder, or thelike is sprayed onto powder, while blowing the powder up by hot air,and, for example, adjustment of spraying conditions, etc. is easy inthis method. Therefore, the fluidized-bed granulation process is themost preferable method.

A person skilled in the art can properly determine which two types ofcomponents among the three components other than the crystallinecellulose are used in the first wet granulation step in the method ofthe present invention, depending on their types, amounts, etc. Forexample, the first wet granulation step can be carried out by usingeither the first or second disintegrator component, and the excipient.

As to specific embodiments of the first method, for example, (1) amethod in which two components of a first disintegrator component (or asecond disintegrator component) and an excipient are used in the firstwet granulation step, and the second disintegrator component (or thefirst disintegrator component) is used in the second wet granulationstep (Examples 1, 3 and 4); (2) a method in which two components of thefirst and second disintegrator components are used in the first wetgranulation step, and an excipient is used in the second wet granulationstep (Example 2); and (3) a method in which two components of the firstdisintegrator component (or the second disintegrator component) and anexcipient are used in the first wet granulation step, and two componentsof the second disintegrator component (or the first disintegratorcomponent) and an excipient are used in the second wet granulation step(Examples 5 to 7) can be mentioned.

Moreover, in the second method of the present invention, a crystallinecellulose is mixed with other component(s) to thereby produce granulesin at least either the first wet granulation step or the second wetgranulation step. For example, either the first disintegrator componentor the second disintegrator component, an excipient and a crystalcellulose can be used to carry out the first wet granulation step, andthe remaining disintegrator component can be further added thereto inthe second wet granulation step. Alternatively, either the firstdisintegrator component or the second disintegrator component and anexcipient can be used to carry out the first wet granulation step, and acrystal cellulose and the remaining disintegrator component can befurther added thereto in the second wet granulation step.

Furthermore, also in the third method of the present invention, a personskilled in the art can properly determine which two types of componentsamong the three components other than the crystalline cellulose are usedin the first wet granulation step, depending on their types, amounts,etc. For example, the first wet granulation step can be carried out byusing either the first disintegrator component or the seconddisintegrator component and the excipient.

Various types of optional components, other than the above-describedfour components, which can be appropriately included in thedisintegrative particulate composition of the present invention andwhich have been known to a person skilled in the art, may be properlyadded in the first and/or second wet granulation step. Alternatively,these optional components may also be added and mixed in an appropriategranulation step of the third step or subsequent steps.

Furthermore, a person skilled in the art can properly determine variousconditions such as the spraying speed, the supply air temperature, theexhaust temperature, and the air supply rate, depending on types oramounts of components, etc.

In both of the first wet granulation step and the second wet granulationstep according to the fluidized-bed granulation process, as a medium forthe spray liquid, a solvent acceptable in pharmaceuticals or foods, suchas water, ethanol, methanol or acetone, can be mentioned. Alternatively,as the spray liquid, for example, an aqueous solution in which less than10% of the component(s) for the disintegrative particulate compositionis dissolved can be mentioned, and, in particular, water or such anaqueous solution is preferable.

Furthermore, the present invention also relates to a disintegrativeparticulate composition obtained by the above-described productionmethod of the present invention, and an orally-disintegrating tabletincluding the disintegrative particulate composition and a medicinalingredient. The orally-disintegrating tablet can include otherpharmaceutically-acceptable optional components such as excipients,surfactants, lubricants, acidulants, sweeteners, corrigents, flavoringagents, colorants, and stabilizing agents, when needed. As theseoptional components, for example, appropriate ingredients described in“Japanese Pharmaceutical Excipients Directory” (YAKUJI NIPPO LIMITED) orthe Japanese Pharmacopoeia can be used. In addition, types of themedicinal ingredient and auxiliary agents included therein are notparticularly limited. Also, the blending ratios of the disintegrativeparticulate composition, the medicinal ingredient and optionalcomponents are not particularly limited as long as the expected effectsof the present invention are brought about, and the blending ratios canproperly be determined by a person skilled in the art. Theorally-disintegrating tablet can be formulated by any methods known to aperson skilled in the art, for example, by tableting.

As already described above, the orally-disintegrating tablet of thepresent invention has superior tablet hardness and disintegrability. Aspreferable values, the orally-disintegrating tablet may be characterizedby having a hardness of 45 to 100 N, preferably 50 to 150 N, morepreferably 70 to 150 (N), still more preferably 80 to 150 N, and byhaving a disintegration time in water of 10 to 30 seconds, preferably 10to 24 seconds, more preferably 10 to 20 seconds, and by having adisintegration time in the oral cavity of 10 to 30 seconds, morepreferably 10 to 21 seconds.

In addition, contents of all related art documents cited in the presentspecification are incorporated herein by reference.

Hereinafter, the present invention will more specifically be describedwith reference to Examples. However, the present invention is notconsidered to be limited to the Examples.

EXAMPLES Evaluation on Hardness and Disintegrability Tests

With respect to each of tablets obtained in Examples and ComparativeExamples, the hardness, the disintegration time in water and thedisintegration time in the oral cavity were measured based on themethods described below. The results of measured hardnesses anddisintegration times are shown in Tables 1 to 6.

In addition, values of these physical properties were measured based onthe following conditions/methods.

Hardness: a hardness (kgf) was measured with a Kiya hardness tester(Fujiwara Scientific Company Co., Ltd.), and the hardness was calculatedin accordance with the following formula.

Hardness(N)=measured hardness(kgf)×9.8

Disintegration time in water: a disintegration time in water wasmeasured with a disintegration tester (NT-4HF, TOYAMA SANGYO CO., LTD.)in accordance with the method described in the Japanese Pharmacopoeia(however, an auxiliary disk was not used).

The measurements for the hardness and disintegration time were eachrepeated six times, and average values thereof were regarded asmeasurement results.

Disintegration time in the oral cavity: one tablet was taken in the oralcavity, and, while keeping a state in which the tablet was placedbetween the tongue and the upper jaw without applying any pressurethereto, the time required for the tablet to be completely disintegratedwas measured. The measurements were each repeated three times by adultsof both sexes, and average values thereof were regarded as measurementresults.

The First Method of the Present Invention Example 1

As the first wet granulation step, 375 g of mannitol (D-mannitol, MerckLtd.) and 100 g of carmellose (NS-300, GOTOKU CHEMICAL CO., LTD.) werecharged to a fluidized-bed granulator (LAB-1, Powrex Corporation), and240 g of purified water was sprayed onto the resulting mixture at a rateof 24 g/minute to thereby granulate the mixture. Further, as the secondwet granulation step, 20 g of crospovidone (Polyplasdone INF-10, ISPJapan) was added to the resulting granules, and 300 g of purified waterwas sprayed thereto at 8 g/minute to thereby obtain granules (adisintegrative particulate composition of the present invention). 0.5parts of magnesium stearate (Wako Pure Chemical Industries, Ltd.) wasadded to 99.5 parts of the obtained granules, and these were mixed. Themixture was then subjected to tableting at a tablet compression force of6.6 kN with a hydraulic hand press (Osaka Jack Co., Ltd.) to therebyobtain tablets having a diameter of 8.0 mm, R6.5, and a weight of 250mg. In addition, the granules had the following values for physicalproperties: (1) an average particle size of 70 microns and (2) a watercontent of 1.4% by weight.

Example 2

As the first wet granulation step, 100 g of carmellose (NS-300, GOTOKUCHEMICAL CO., LTD.) and 20 g of crospovidone (Polyplasdone INF-10, ISPJapan) were charged to a fluidized-bed granulator (LAB-1, PowrexCorporation), and 240 g of purified water was sprayed onto the resultingmixture at a rate of 12 g/minute to thereby granulate the mixture.Further, as the second wet granulation step, 375 g of mannitol(D-mannitol, Merck Ltd.) was added to the resulting granules, and 300 gof purified water was sprayed thereto at 18 g/minute to thereby obtaingranules (a disintegrative particulate composition of the presentinvention). The obtained granules were used for tableting in the samemanner as Example 1, and tablets having a diameter of 8.0 mm, R6.5, anda weight of 250 mg were obtained. In addition, the granules had thefollowing values for physical properties: (1) an average particle sizeof 98 microns and (2) a water content of 0.94% by weight.

Example 3

As the first wet granulation step, 375 g of mannitol (D-mannitol, MerckLtd.) and 20 g of crospovidone (Polyplasdone INF-10, ISP Japan) werecharged to a fluidized-bed granulator (LAB-1, Powrex Corporation), and240 g of purified water was sprayed onto the resulting mixture at a rateof 12 g/minute to thereby granulate the mixture. Further, as the secondwet granulation step, 100 g of carmellose (NS-300, GOTOKU CHEMICAL CO.,LTD.) was added to the resulting granules, and 300 g of purified waterwas sprayed thereto at 24 g/minute to thereby obtain granules (adisintegrative particulate composition of the present invention). Theobtained granules were used for tableting in the same manner as Example1, and tablets having a diameter of 8.0 mm, R6.5, and a weight of 250 mgwere obtained. In addition, the granules had the following values forphysical properties: (1) an average particle size of 73 microns and (2)a water content of 1.1% by weight.

Comparative Example 1

375 g of mannitol (D-mannitol, Merck Ltd.), 100 g of carmellose (NS-300,GOTOKU CHEMICAL CO., LTD.) and 20 g of crospovidone (PolyplasdoneINF-10, ISP Japan) were charged to a fluidized-bed granulator (LAB-1,Powrex Corporation), and 240 g of purified water was sprayed onto theresulting mixture at a rate of 12 g/minute to thereby obtain granules inone granulation step. The obtained granules were used for tableting inthe same manner as Example 1, and tablets having a diameter of 8.0 mm,R6.5, and a weight of 250 mg were obtained.

Comparative Example 2

Granules were obtained in the same conditions as Comparative Example 1except that 240 g of purified water was sprayed at a rate of 24g/minute. The obtained granules were used for tableting in the samemanner as Example 1, and tablets having a diameter of 8.0 mm, R6.5, anda weight of 250 mg were obtained.

Example 4

Granules were obtained in the same conditions as Example 1 except that370 g of D-mannitol and 5 g of erythritol were used instead of 375 g ofD-mannitol in Example 1. The obtained granules were used for tabletingin the same manner as Example 1. Consequently, tablets having a diameterof 8.0 mm, R6.5, and a weight of 250 mg were obtained. In addition, thegranules had the following values for physical properties: (1) aparticle size of 90 microns and (2) a water content of 1.3% by weight.

Comparative Example A

Granules were obtained in one granulation step in the same conditions asComparative Example 1 except that 370 g of D-mannitol and 5 g oferythritol were used instead of 375 g of D-mannitol in ComparativeExample 1. The obtained granules were used for tableting in the samemanner as Example 1. Consequently, tablets having a diameter of 8.0 mm,R6.5, and a weight of 250 mg were obtained.

Example 5

Granules were obtained in the same conditions as Example 1 except thatthe amount of D-mannitol in the first wet granulation step in Example 1was changed to 356 g and that 19 g of trehalose and 20 g of crospovidonewere used in the second wet granulation step. The obtained granules wereused for tableting in the same manner as Example 1. Consequently,tablets having a diameter of 8.0 mm, R6.5, and a weight of 250 mg wereobtained. In addition, the granules had the following values forphysical properties: (1) a particle size of 141 microns and (2) a watercontent of 2.1% by weight.

Comparative Example B

Granules were obtained in one granulation step in the same conditions asComparative Example 1 except that 356 g of D-mannitol and 19 g oftrehalose were used instead of 375 g of D-mannitol in ComparativeExample 1. The obtained granules were used for tableting in the samemanner as Example 1. Consequently, tablets having a diameter of 8.0 mm,R6.5, and a weight of 250 mg were obtained.

Example 6

Tableting was carried out in the same manner as Example 1 except thatthe amount of D-mannitol in the first wet granulation step in Example 1was changed to 300 g and that 75 g of maltitol and 20 g of crospovidonewere used in the second wet granulation step. Consequently, tabletshaving a diameter of 8.0 mm, R6.5, and a weight of 250 mg were obtained.In addition, the granules had the following values for physicalproperties: (1) a particle size of 143 microns and (2) a water contentof 1.6%.

Comparative Example C

Granules were obtained in one granulation step in the same conditions asComparative Example 1 except that 300 g of D-mannitol and 75 g ofmaltitol were used instead of 375 g of D-mannitol in ComparativeExample 1. The obtained granules were used for tableting in the samemanner as Example 1. Consequently, tablets having a diameter of 8.0 mm,R6.5, and a weight of 250 mg were obtained.

Example 7

Granules were obtained in the same conditions as Example 1 except thatthe amount of D-mannitol in the first wet granulation step in Example 1was changed to 356 g and that 19 g of sorbitol and 20 g of crospovidonewere used in the second wet granulation step. The obtained granules wereused for tableting in the same manner as Example 1. Consequently,tablets having a diameter of 8.0 mm, R6.5, and a weight of 250 mg wereobtained. In addition, the granules had the following values forphysical properties: (1) a particle size of 188 microns and (2) a watercontent of 1.9%.

Comparative Example D

Granules were obtained in one granulation step in the same conditions asComparative Example 1 except that 356 g of D-mannitol and 19 g ofsorbitol were used instead of 375 g of D-mannitol in ComparativeExample 1. The obtained granules were used for tableting in the samemanner as Example 1. Consequently, tablets having a diameter of 8.0 mm,R6.5, and a weight of 250 mg were obtained.

TABLE 1 Production methods Compar- Compar- for disintegrative ativeative particulate com- Exam- Exam- Exam- Exam- Exam- position ple 1 ple2 ple 3 ple 1 ple 2 Tablet compression 6.6 6.6 6.6 6.6 6.6 force (KN)Hardness (N) 58 50 52 34 40 Disintegrative time 15 13 13 21 17 in water(seconds)

In addition, each of the disintegrative particulate compositionsobtained by the methods of Examples 1, 2 and 3 was subjected totableting in the same method described in each of the Examples exceptthat the tablet compression force was changed to 8.3 KN. In that case,results obtained by subjecting the obtained tablets to the measurementsof the hardness and disintegration times in water in the same manner asthe cases in Table 1 are shown in Table 2.

TABLE 2 Production methods for disintegrative particulate com- positionExample 1 Example 2 Example 3 Tablet compression 8.3 8.3 8.3 force (KN)Hardness (N) 84 68 72 Disintegrative time 17 12 16 in water (seconds)

Furthermore, each of the disintegrative particulate compositionsobtained by the methods of Examples 3 to 7 and corresponding ComparativeExamples A to D was subjected to tableting in the same method describedin each of the Examples except that the tablet compression force waschanged to 8.3 KN. In that case, results obtained by subjecting theobtained tablets to the measurements of the hardness and disintegrationtimes in water in the same manner as the cases in Table 1 are shown inTable 3.

TABLE 3 Tablet compression forces Excipients: mannitol 6.6 8.3 anderythritol kN kN Two-stage granulation Hardness (N) 49 68 (Example 4)Disintegration time 15 17 in water (s) One-stage granulation Hardness(N) 30 46 (Comparative Example Disintegration time 12 15 A) in water (s)Excipients: mannitol Tablet compression force and trehalose 6.6 kNTwo-stage granulation Hardness (N) 64 (Example 5) Disintegration time 23in water (s) One-stage granulation Hardness (N) 44 (Comparative ExampleDisintegration time 18 B) in water (s) Tablet compression forces 6.0 8.0kN kN Excipients: mannitol and maltitol Two-stage granulation Hardness(N) 50 63 (Example 6) Disintegration time 24 28 in water (s) One-stagegranulation Hardness (N) 63 73 (Comparative Example Disintegration time115 >200 C) in water (s) Excipients: mannitol and sorbitol Two-stagegranulation Hardness (N) 46 56 (Example 7) Disintegration time 19 23 inwater (s) One-stage granulation Hardness (N) 28 37 (Comparative ExampleDisintegration time 16 18 D) in water (s)

Based on the results shown in Tables 1 to 3, it was proven that,regardless of which two types of components among the firstdisintegrator component, the second disintegrator component and theexcipient were used in the first wet granulation step, the tabletsobtained by using granules (disintegrative particulate compositions ofthe present invention) produced by the methods of the present inventionincluding the first wet granulation step and the second wet granulationstep in Examples 1 to 7 had superior tablet hardness anddisintegrability as well as superior moldability through which highertablet hardness was obtained by smaller tablet compression forces, ascompared with tablets obtained by using granules which were produced byconventional methods of granulating the components together in one step.

The Second Method of the Present Invention Example 8 Production of aDisintegrative Particulate Composition

As the first wet granulation step, 280 g of mannitol (D-mannitol, MerckLtd.), 75 g of carmellose (NS-300, GOTOKU CHEMICAL CO., LTD.) and 100 gof a crystalline cellulose (CEOLUS PH-101, Asahi Kasei Chemicals Corp.)were charged to a fluidized-bed granulator (LAB-1, Powrex Corporation),and 240 g of purified water was sprayed onto the resulting mixture at arate of 24 g/minute to thereby granulate the mixture. Further, as thesecond wet granulation step, 40 g of crospovidone (Polyplasdone INF-10,ISP Japan) was added to the resulting granules, and 300 g of purifiedwater was sprayed thereto at 10 g/minute to thereby obtain granules (adisintegrative particulate composition of the present invention). 0.5parts by weight of magnesium stearate (Taihei Chemical Industrial Co.Ltd.) was added to 99.5 parts by weight of the obtained granules, andthese were mixed. The mixture was then subjected to tableting at tabletcompression forces of 6.0 kN and 8.0 kN with a simple tableting machine(ICHIHASHI-SEIKI Co., Ltd.) to thereby obtain tablets having a diameterof 8.0 mm, R6.5, and a weight of 250 mg. In addition, the granules hadthe following values for physical properties: (1) an average particlesize of 93 microns and (2) a water content of 2.3% by weight.

Example 9 Production of a Disintegrative Particulate Composition

As the first wet granulation step, 280 g of mannitol (D-mannitol, MerckLtd.) and 75 g of carmellose (NS-300, GOTOKU CHEMICAL CO., LTD.) werecharged to a fluidized-bed granulator (LAB-1, Powrex Corporation), and227 g of purified water was sprayed onto the resulting mixture at a rateof 24 g/minute to thereby granulate the mixture. Further, as the secondwet granulation step, 40 g of crospovidone (Polyplasdone INF-10, ISPJapan) and 100 g of a crystalline cellulose (CEOLUS PH-101, Asahi KaseiChemicals Corp.) were added to the resulting granules, and 300 g ofpurified water was sprayed thereto at 10 g/minute to thereby obtaingranules (a disintegrative particulate composition of the presentinvention). The obtained granules were used for tableting in the samemanner as Example 8 to thereby obtain tablets having a diameter of 8.0mm, R6.5, and a weight of 250 mg. In addition, the granules had thefollowing values for physical properties: (1) an average particle sizeof 93 microns and (2) a water content of 1.8% by weight.

Example 10 Production of a Disintegrative Particulate Composition

Granulation was carried out in the same conditions as Example 8 exceptthat the amount of D-mannitol and the amount of the crystallinecellulose in the first wet granulation step of Example 8 were changed to255 g and 125 g, respectively, to thereby obtain granules (adisintegrative particulate composition of the present invention). Theobtained granules were used for tableting in the same manner as Example8. Consequently, tablets having a diameter of 8.0 mm, R6.5, and a weightof 250 mg were obtained. In addition, the granules had the followingvalues for physical properties: (1) an average particle size of 87microns and (2) a water content of 2.2% by weight.

Example 11 Production of a Disintegrative Particulate Composition

Granulation was carried out in the same conditions as Example 8 exceptthat the amount of D-mannitol in the first wet granulation step inExample 8 was changed to 270 g and that the amount of crospovidone waschanged to 50 g in the second wet granulation step, to thereby obtaingranules (a disintegrative particulate composition of the presentinvention). The obtained granules were used for tableting in the samemanner as Example 8. Consequently, tablets having a diameter of 8.0 mm,R6.5, and a weight of 250 mg were obtained. In addition, the granuleshad the following values for physical properties: (1) an averageparticle size of 100 microns and (2) a water content of 2.1% by weight.

Example 12 Production of a Disintegrative Particulate Composition

As the first wet granulation step, 280 g of mannitol (D-mannitol, MerckLtd.) and 40 g of crospovidone (Polyplasdone INF-10, ISP Japan) werecharged to a fluidized-bed granulator (LAB-1, Powrex Corporation), and179 g of purified water was sprayed onto the resulting mixture at a rateof 12 g/minute to thereby granulate the mixture. Further, as the secondwet granulation step, 75 g of carmellose (NS-300, GOTOKU CHEMICAL CO.,LTD.) and 100 g of a crystalline cellulose (CEOLUS PH-101, Asahi KaseiChemicals Corp.) were added to the resulting granules, and 300 g ofpurified water was sprayed thereto at 12 g/minute to thereby obtaingranules (a disintegrative particulate composition of the presentinvention). The obtained granules were used for tableting in the samemanner as Example 8 to thereby obtain tablets having a diameter of 8.0mm, R6.5, and a weight of 250 mg. In addition, the granules had thefollowing values for physical properties: (1) an average particle sizeof 81 microns and (2) a water content of 2.5% by weight.

Example 13 Production of a Disintegrative Particulate Composition

As the first wet granulation step, 140 g of mannitol (D-mannitol, MerckLtd.), 100 g of a crystalline cellulose (CEOLUS PH-101, Asahi KaseiChemicals Corp.) and 40 g of crospovidone (Polyplasdone INF-10, ISPJapan) were charged to a fluidized-bed granulator (LAB-1, PowrexCorporation), and 155 g of purified water was sprayed onto the resultingmixture at a rate of 12 g/minute to thereby granulate the mixture.Further, as the second wet granulation step, 140 g of mannitol(D-mannitol, Merck Ltd.) and 75 g of carmellose (NS-300, GOTOKU CHEMICALCO., LTD.) were added to the resulting granules, and 300 g of purifiedwater was sprayed thereto at 12 g/minute to thereby obtain granules (adisintegrative particulate composition of the present invention). 0.5parts by weight of magnesium stearate (Taihei Chemical Industrial Co.Ltd.) was added to 99.5 parts by weight of the obtained granules, andthese were mixed. The mixture was then subjected to tableting at tabletcompression forces of 6.0 kN and 8.0 kN with a simple tableting machine(HANDTAB-100, ICHIHASHI-SEIKI Co., Ltd.) to thereby obtain tabletshaving a diameter of 8.0 mm, R6.5, and a weight of 250 mg. In addition,the granules had the following values for physical properties: (1) anaverage particle size of 90 microns and (2) a water content of 2.5% byweight.

Comparative Example 3

280 g of mannitol (D-mannitol, Merck Ltd.), 75 g of carmellose (NS-300,GOTOKU CHEMICAL CO., LTD.), 100 g of a crystalline cellulose (CEOLUSPH-101, Asahi Kasei Chemicals Corp.) and 40 g of crospovidone(Polyplasdone INF-10, ISP Japan) were charged to a fluidized-bedgranulator (LAB-1, Powrex Corporation), and 300 g of purified water wassprayed onto the resulting mixture at a rate of 12 g/minute to therebyobtain granules in one granulation step. The obtained granules were usedfor tableting in the same manner as Example 8, and, consequently,tablets having a diameter of 8.0 mm, R6.5, and a weight of 250 mg wereobtained.

TABLE 4 Tablets Example 8 Example 9 Example 10 Example 11 Tablet 6.0 8.06.0 8.0 6.0 8.0 compression force (kN) Hardness (N) 90 116 83 108 104 91Disintegration 16 24 13 17 15 15 time in water (seconds) ComparativeTablets Example 3 Tablet compression 6.0 8.0 force (kN) Hardness (N) 5981 Disintegration time 12 13 in water (seconds)

The disintegration times in water of tablets obtained in Examples 8 to13 and Comparative Example 3 were below 30 seconds, and it was provedthat Examples 8 to 13 substantially maintained sufficientdisintegrability regardless of their higher tablet hardness, comparedwith Comparative Example 3.

The Third Method of the Present Invention Example 14 Production of anOrally-Disintegrating Tablet

As the first wet granulation step, 75 g of carmellose (NS-300, GOTOKUCHEMICAL CO., LTD.) and 40 g of crospovidone (Polyplasdone INF-10, ISPJapan) were charged to a fluidized-bed granulator (LAB-1, PowrexCorporation), and 240 g of purified water was sprayed onto the resultingmixture at a rate of 12 g/minute to thereby granulate the mixture.Further, as the second wet granulation step, 380 g of mannitol(D-mannitol, Merck Ltd.) was added to the resulting granules, and 300 gof purified water was sprayed thereto at 18 g/minute to thereby obtaingranules (I). In addition, the granules (I) had the following values forphysical properties: (1) an average particle size of 108 microns and (2)a water content of 0.9% by weight. As the third step, 49.5 parts byweight of the granules (I) obtained in this way, and 20 parts by weightof a crystalline cellulose (CEOLUS PH-101, Asahi Kasei Chemicals Corp.)were mixed to thereby obtain a disintegrative particulate composition ofthe present invention. In addition, this disintegrative particulatecomposition had the following values for physical properties: (1) anaverage particle size of 98 microns and (2) a water content of 2.0% byweight. Further, 30 parts by weight of N-(4-hydroxyphenyl)acetamide(Acetaminophen), and 0.5 parts by weight of magnesium stearate (TaiheiChemical Industrial Co. Ltd.) were added to 69.5 parts by weight of thedisintegrative particulate composition, and these were mixed. Themixture was then subjected to tableting at tablet compression forces of6.6 kN and 8.3 kN with a hydraulic hand press (Osaka Jack Co., Ltd.) tothereby obtain tablets having a diameter of 8.0 mm, R6.5, and a weightof 250 mg.

Example 15 Production of an Orally-Disintegrating Tablet

As a third step, 39.5 parts by weight of the granules (I) obtained inExample 14 and 30 parts by weight of a crystalline cellulose (CEOLUSPH-101, Asahi Kasei Chemicals Corp.) were mixed to obtain adisintegrative particulate composition of the present invention. Inaddition, this disintegrative particulate composition had the followingvalues for physical properties: (1) an average particle size of 88microns and (2) a water content of 2.3% by weight. 30 parts by weight ofacetaminophen, and 0.5 parts by weight of magnesium stearate (TaiheiChemical Industrial Co. Ltd.) were added to 69.5 parts by weight of thedisintegrative particulate composition, and these were mixed. Themixture was then subjected to tableting at tablet compression forces of6.6 kN and 8.3 kN with a hydraulic hand press (Osaka Jack Co., Ltd.) tothereby obtain tablets having a diameter of 8.0 mm, R6.5, and a weightof 250 mg.

Example 16 Production of an Orally-Disintegrating Tablet

As a third step, 69.5 parts by weight of the granules (I) obtained inExample 14 and 30 parts by weight of a crystalline cellulose (CEOLUSPH-101, Asahi Kasei Chemicals Corp.) were mixed to obtain adisintegrative particulate composition of the present invention. Inaddition, this disintegrative particulate composition had the followingvalues for physical properties: (1) an average particle size of 102microns and (2) a water content of 1.8% by weight. 0.5 parts by weightof magnesium stearate (Taihei Chemical Industrial Co. Ltd.) was added tothe disintegrative particulate composition, and these were mixed. Themixture was then subjected to tableting at tablet compression forces of6.6 kN and 8.3 kN with a hydraulic hand press (Osaka Jack Co., Ltd.) tothereby obtain tablets having a diameter of 8.0 mm, R6.5, and a weightof 250 mg.

Example 17 Production of an Orally-Disintegrating Tablet

Granulation was carried out in the same conditions as Example 14 exceptthat 40 g of carboxymethylcellulose calcium (ECG-505, GOTOKU CHEMICALCO., LTD.) was used instead of 40 g of crospovidone in the first wetgranulation step in Example 14, thereby obtaining granules (II). Inaddition, the granules (II) had the following values for physicalproperties: (1) an average particle size of 89 microns and (2) a watercontent of 1.1%. As a third step, 79.5 parts by weight of the obtainedgranules (II) and 20 parts by weight of a crystalline cellulose (CEOLUSPH-101, Asahi Kasei Chemicals Corp.) were mixed to thereby obtain adisintegrative particulate composition of the present invention. Inaddition, this disintegrative particulate composition had the followingvalues for physical properties: (1) an average particle size of 102microns and (2) a water content of 2.0% by weight. Further, 0.5 parts byweight of magnesium stearate (Taihei Chemical Industrial Co. Ltd.) wasadded to the disintegrative particulate composition, and these weremixed. The mixture was then subjected to tableting at tablet compressionforces of 6.0 kN and 8.0 kN with a simple tableting machine(HANDTAB-100, ICHIHASHI-SEIKI Co., Ltd.) to thereby obtain tabletshaving a diameter of 8.0 mm, R6.5, and a weight of 250 mg.

Example 18 Production of an Orally-Disintegrating Tablet

Granulation was carried out in the same conditions as Example 14 exceptthat 40 g of croscarmellose sodium (ND-2HS, Asahi Kasei Chemicals Corp.)was used instead of 40 g of crospovidone in the first wet granulationstep in Example 14, thereby obtaining granules (III). In addition, thegranules (III) had the following values for physical properties: (1) anaverage particle size of 89 microns and (2) a water content of 1.0%. Asa third step, 79.5 parts by weight of the obtained granules (III) and 20parts by weight of a crystalline cellulose (CEOLUS PH-101, Asahi KaseiChemicals Corp.) were mixed to thereby obtain a disintegrativeparticulate composition of the present invention. In addition, thisdisintegrative particulate composition had the following values forphysical properties: (1) an average particle size of 95 microns and (2)a water content of 2.1% by weight. Further, 0.5 parts by weight ofmagnesium stearate (Taihei Chemical Industrial Co. Ltd.) was added tothe disintegrative particulate composition, and these were mixed. Themixture was then subjected to tableting at tablet compression forces of6.0 kN and 8.0 kN with a simple tableting machine (HANDTAB-100,ICHIHASHI-SEIKI Co., Ltd.) to thereby obtain tablets having a diameterof 8.0 mm, R6.5, and a weight of 250 mg.

Comparative Example 4

99.5 parts by weight of the granules (I) obtained in Example 14 and 0.5parts by weight of magnesium stearate (Taihei Chemical Industrial Co.Ltd.) were mixed, and tablets were obtained in the same manner asExample 1.

Comparative Example 5

99.5 parts by weight of the granules (II) obtained in Example 17 and 0.5parts by weight of magnesium stearate (Taihei Chemical Industrial Co.Ltd.) were mixed, and tablets were obtained in the same manner asExample 1.

Comparative Example 6

99.5 parts by weight of the granules (III) obtained in Example 18 and0.5 parts by weight of magnesium stearate (Taihei Chemical IndustrialCo. Ltd.) were mixed, and tablets were obtained in the same manner asExample 1.

TABLE 5 Unit (parts by weight) Granule Crystalline Magnesium (I)cellulose Acetaminophen stearate Example 14 49.5 20 30 0.5 Example 1539.5 30 30 0.5 Example 16 69.5 30 0 0.5 Example 17 79.5 20 0 0.5 Example18 79.5 20 0 0.5 Comparative 99.5 0 0 0.5 Example 4 Comparative 99.5 0 00.5 Example 5 Comparative 99.5 0 0 0.5 Example 6

TABLE 6 Tablets Example 14 Example 15 Example 16 Tablet compression 6.68.3 6.6 8.3 6.6 8.3 force (kN) Hardness (N) 21 35 35 47 73 97Disintegration time 11 12 11 12 13 17 in water (seconds) Example ExampleComparative Comparative Comparative Tablets 17 18 Example 4 Example 5Example 6 Tablet compression 8.0 8.0 6.6 8.3 8.3 8.3 force (kN) Hardness(N) 45 48 50 68 37 39 Disintegration time 11 12 13 12 15 16 in water(seconds)

When comparing Examples 16 to 18 with Comparative Examples 4 to 6,respectively, based on the results shown in Table 6, it was proven thatorally-disintegrating tables having higher tablet hardness whilemaintaining sufficient disintegrability could be produced by usingdisintegrative particulate compositions which were obtained by furthermixing a crystalline cellulose, as a third step, into granules (I) to(III) produced by the methods of the present invention includingtwo-stage wet granulation steps including the first and second wetgranulation steps, as compared with the Comparative Examples.

INDUSTRIAL APPLICABILITY

The present invention significantly contributes to research anddevelopment of orally-disintegrating tablets having excellent tablethardness and disintegrability.

What is claimed is:
 1. An method of producing a disintegrativeparticulate composition comprising: three components consisting of afirst disintegrator component of an acid-type carboxymethylcellulose, asecond disintegrator component other than the acid-typecarboxymethylcellulose and an excipient, the method characterized bycomprising: a first wet granulation step using any two of the threecomponents; and using at least granules obtained in the first wetgranulation step and the remaining component not used in the first wetgranulation step.
 2. The method of producing a disintegrativeparticulate composition according to claim 1, wherein the disintegrativeparticulate composition further comprises a crystalline cellulose as afourth component, and the method comprises a first wet granulation stepforms granules using any two or three of the four components and asecond wet granulation step using at least the granules obtained in thefirst wet granulation step and the remaining one or two of the fourcomponents not used in the first wet granulation step.
 3. The method ofproducing a disintegrative particulate composition according to claim 1,wherein the disintegrative particulate composition further comprises acrystalline cellulose as a fourth component, and the method comprises afirst wet granulation step using any two of the three components otherthan the crystalline cellulose, a second wet granulation step using atleast the granules obtained in the first wet granulation step and theremaining one component not used in the first wet granulation step, anda third step of mixing the crystalline cellulose into granules obtainedin the second wet granulation step.
 4. The method of producing adisintegrative particulate composition according to claim 1, wherein anyof the three components is used only in one granulation step.
 5. Themethod of producing a disintegrative particulate composition accordingto claim 4, wherein the method comprises the first wet granulation stepusing any two of the three components and the second wet granulationstep using only the granules obtained in the first wet granulation stepand the remaining one component not used in the first wet granulationstep.
 6. The method of producing a disintegrative particulatecomposition according to claim 1, wherein the second disintegratorcomponent is one or more selected from crospovidone, croscarmellosesodium, carboxymethyl starch sodium, low substitutedhydroxypropylcellulose, and carboxymethylcellulose calcium.
 7. Themethod of producing a disintegrative particulate composition accordingto claim 1, wherein the excipient is a sugar or sugar alcohol.
 8. Themethod of producing a disintegrative particulate composition accordingto claim 1, wherein the first and second wet granulation steps arecarried out by a fluidized-bed granulation process.
 9. The method ofproducing a disintegrative particulate composition according to claim 1,wherein the first wet granulation step is carried out using the first orsecond disintegrator component and the excipient.
 10. The method ofproducing a disintegrative particulate composition according to claim 1,wherein a spray liquid is water or an aqueous solution in which lessthan 10% of components for the disintegrative particulate compositionare dissolved.
 11. A disintegrative particulate composition which isobtained by the method for producing a disintegrative particulatecomposition according to claim
 1. 12. An orally-disintegrating tablet,comprising the disintegrative particulate composition according to claim11 and a medicinal ingredient.
 13. The orally-disintegrating tabletaccording to claim 12, having a hardness of 45 to 100 N and adisintegration time in water of 10 to 30 seconds.
 14. Theorally-disintegrating tablet according to claim 13, having a hardness of50 to 100 N, a disintegration time in water of 10 to 30 seconds and adisintegration time in the oral cavity of 10 to 30 seconds.